Pyschological Stress can induce Oxidative Stress-mediated Vascular Injury

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1 Pyschological Stress can induce Oxidative Stress-mediated Vascular Injury Ick-Mo Chung, MD, PhD Cardiology Division Ewha Womans University

2 Contents Evidence of psychological stress as a risk factor for CAD Possible underlying mechanism by which psychological stress injure the vessel - Oxidative stress : ROCK, RGS - Inflammation

3 Allostatic Load Allostasis: ability to achieve stability through change Allostatic load: long term effect of physiological response to Stress McEwen BS. N Engl J Med 1998;338:171

4 Psychological stress as a risk factor for CVD Psychological stress is estimated as an emerging risk factor for atherosclerosis. - Stress: threatened homeostasis provoked by stressor. - Psychological factors contribute to the development and progression of CAD: depression, anxiety, personality and character traits, social isolation, and chronic life stress Physiological response to stress is mediated by the activation of sympathetic nervous system (SNS) and hypothalamic pituitary adrenal (HPA) axis. Stress can induce inflammation in peripheral organ through neuroendocrine system

5 Social stress and Atherosclerosis in normocholesterolemic monkeys Rate of aggressionφ Severe aggression % Rate of submission Severe submission % Time in affiliation % Stress (n=15) * * 21.0* Control (n=14) Intimal area (mm 2 ) Φ median rates of performance per hour per monkey, * p<0.05 Arteries with plaques 11/15 (stress) vs 4/14 (control) p< stress s control Kaplan JR. Science.1983;220:

6 Anger proneness predicts CHD risk Prospective analysis from the Atherosclerosis Risk In Communities (ARIC) Study Williams JE. Circulation. 2000;101: Aim 1. dose-response relation between anger and CHD risk 2. relation of CHD free survival with anger level Methods Prospective design (median 53 mo, 6yr Max. f/u) ARIC study (n=13,208) white and black men and women (45-64 yr) without CHD 10-item Spielberger Trait Anger Scale CHD events: acute MI/fatal CHD (hard event), silent MI, revascularization procedure

7 CHD event free survival probabilities by Trait Anger scores Normotensive Hypertensive P=NS P=.001 Williams JE. Circulation. 2000;101:

8 Intensive lifestyle changes for reversal of CHD Ornish D. JAMA. 1998;280: Lifestyle Heart Trial (JAMA1983;249:54-9) Comprehensive lifestyle changes (1 yr) without lipid lowering drug could reduce LDL-chol by 37% and reduce frequency of angina attack by 91% Aims Effect of sustained lifestyle changes on risk factors, coronary atherosclerosis, and cardiac events after 4 additional yr. Patients: angiography-proven CAD Pts Intensive Lifestyle Program 10% fat vegetarian diet, moderate aerobic exercise, stress management, smoking cessation, and group psychosocial support for 5 yrs avoid simple sugars, emphasize intake of complex carbohydrates and other whole foods

9 Angina symptoms Cardiac events during 5 yr f/u * * *

10 Mean percentage diameter stenosis P=.001 P=.02 Ornish, D. et al. JAMA 1998;280:

11 Reduction in the incidence of type II DM with lifestyle intervention or metformin Diabetes Prevention Program Research Group N Engl J Med 2002;346:393 Question Does a lifestyle intervention or Tx with metformin prevent or delay the onset of DM? Inclusion criteria BMI: 24, plasma glucose: (AC) mg/dl, PC mg/dl - Standard lifestyle with metforrmin 850 mg bid : food guide pyramid NCEP step 1 diet - Intensive lifestyle modification 16-session curriculum covering diet, exercise, and behavior modification, weight reduction >7% through a healthy low calorie, low fat diet, moderate physical activity s/a brisk walking 150 min /wk

12 Cumulative incidence of DM P<.001 Diabetes Prevention Program Research Group NEJM. 2002;346:

13 MDA final / MDA baseline e-nos mrna/ β actin mrna ** ** MDA * stress losartan ramipril control enos mrna * ** * * NOx final / NOx baseline Immobilization stress induces changes in ROS Plasma NOx ** ** ** * stress losartan ramipril control *p<0.05, **p<0.01, p<0.05 for final vs baseline M±SEM 0.0 stress losartan ramipril control Chung I-M & Kim YM Circ Res 2004;93:1523 (abstr)

14 Changes in Ach-induced arterial relaxation stress losartan ramipril control ** ** ** ** ** ** *p<0.05 **p<0.01 p=0.086 M±SEM Relaxation (%) * ** ** Concentration of Ach (log 10 M)

15 Immobilization stress can enhance expression of VCAM-1 VCAM-1 % VCAM-1 positive cells * *p<0.01 vs stress p=0.086 vs stress * <10% 10% VCAM-1 EC EC Stress SD AA 0 stress losartan ramipril control Control SD AA Bar: 50 μm

16 Effect of CUS on NF-κB activation induced by LPS or saline (SAL) in the frontal cortex (A), hypothalamus (B), or hippocampus (C) Munhoz, C. D. et al. J. Neurosci. 2006;26:

17 Plasma IL-6 and NF-κB DNA Binding in PBMC of Patients With Major Depression After a Psychosocial Stressor Challenge Miller AH, Am J Psychiatry 2006;163:1630

18 Neurogenic Inflammation in Stress Both somatic and autonomic nerves are associated with inflammatory cells, and nervous transmission may result in neurogenic inflammation : Nervous innervation is a requirement for establishing certain inflammatory reaction: eg. rhematoid arthritis Direct linkage between neurogenic stimulation and proinflammatory cytokine release - contributing inflammatory mediators in stress PGE2: + SN ending Neuropeptide Y: cotransmitter of SN innervation promotes SMC proliferation, enhances leukocyte adhesion, platelet aggregation, and MΦ activation CRF: + in SN ending, sensory N, spinal cord Substance P: + in autonomic N, ganglia, spinal cord, IL-6: + in sensory N, autonomic N

19 Vascular Injury mediated through Oxidative Stress Response to injury Hypothesis Injury to the endothelium might precipitate the atherosclerotic process (Virchow R, 1856) Atherosclerotic lesions result from an excessive inflammatoryfibroproliferative response various forms of insult to the endothelium and smooth muscle of the artery wall (Ross R,Nature. 1993) Oxidative stress, an excessive production of ROS outstripping antioxidant defense systems, has been implicated in many pathophysiological conditions in cardiovascular systems (atherosclerosis, hypertension, restenosis, smoking, hypercholesterolemia, DM, hypertension, heart failure), cancer, and neurodegeneration.

20 Vascular ROS 10 x Griendling KK et al. Circulation.2003;108:1912-6

21 Peroxynitrite (ONOO - ) strong oxidant: oxidative damage of DNA, RNA, proteins, lipids Mediator of protein nitration Promotes inflammatory synthesis of prostaglandin by activating cyclooxygenase (COX) Attack prostacyclin synthase (Tyr nitration?): Accumulating PGH 2 can activate thromboxane receptors, thereby promoting vasoconstriction Deactivate anti-inflammatory agents Activate c-jun-nh 2 -terminal kinase (JNK) thereby inducing a wide range of stress-related responses including apoptosis Protective role: microbicidal agent, limit bleeding Beckman JS, Circ Res 2001;89:295

22 Potential sources of ROS * rac1, AngII, TNF-α, thrombin, PDGF * Griendling KK et al. Circulation.2003;108:1912-6

23 Consequences of NAD(P)H oxidase activation Harrison DG, 2003;24:

24 Peroxynitrite can increase MMP2 activity Effect of ONOO - on gelatinolytic activity in human SMCs Effect of ONOO - on collagenolytic activity in human SMCs Gallis ZS, J Clin Invest 1996;98:2572 Fluorographic image of 3 H-type IV collagen

25 Regulation of myosin II in SMC and non-muscle cells AT1R IL-1β Somlyo AP. J Phys 2000;522:1777

26 Regulation of enos by ROCK Liao JK, Am J Physiol Cell Physiol 290: C661-C668, 2006

27 Ang II-mediated coronary vascular hypertrophy: role of Rho-kinase Shimokawa H. Circ Res 2003;93:767-75

28 Ang II-mediated vascular macrophage accumulation Role of Rho-kinase Shimokawa H. Circ Res 2003;93:767-75

29 Ang II-mediated NADPH oxidase: Role of Rho-kinase Shimokawa H. Circ Res 2003;93:767-75

30 ROCK inhibition improves endothelial function in CAD Nohria A. et al. Circ Res. 2006;99:1426

31 Active ROCK-α associates with Insulin Receptor Substrate-1 and inhibits insulin signaling in VSMCs Begum N, J Biol Chem 2002;277:6214

33 Ang II induce expression and activation of ROCK via NF-κB in vivo Shimokawa H, J Mol Cell Cardiol 2004;37:537

34 AbdAlla S et al. Cell 2004;119:343-54

35 Mononuclear phagocytes in atherogenesis Libby P. Nature 2002;420:868

36 G-Protein coupled Receptor (G-PCR) Signaling Model 23 known Gα protein Gα(s/olf) Gα(i1/i2/i3/t-rod/t-con/gust/z) Gα(q/11/14/16) Gα(12/13) AC GIRK, ERK1/2, JNK, PI3Kr, PLCβ/-ε MAPKs etc. McCudden CR. CMLS 2005;62:551

37 GPCR signaling & Cariovascular disease G αq transgenic overexpression mediates changes in heart function leading to hypertrophy (D Angello D. PNAS197;94:8121). RGS2+/- and RGS2-/- are hypertensive and show prolonged response of the vasculature to vasoconstrictor in vivo. (Heximer SP, J Clin Invest 2003) Transgenic overexpression of RGS4 in aortic coarctation mice model reduced ventricular hypertrophy and rapid decompensation (Rogers JH. J Clin Invest 1999)

38 Differential expression of RGS proteins in each vascular segments mrna fold change RGS1 RGS2 RGS3 RGS4 RGS8 RGS16 RGS5 * RGS5 mrna fold change p<0.05 vs TA of * RGS2 RGS3 RGS4 RGS5 RGS16 0 CCA TA AA CIA MA PA IVC 0 Chung I-M & Schwartz SM. AHA 2006

39 Decreased arterial contraction in abdominal vs thoracic aorta Force (mn) A TA, AA * * * Force (mn) B [Angiotensin II] (nm) [Phenylephrine] (µm)

40 AT1R-stimulated NFAT Activation in Cardiac Fibroblast Kurose H. J Biol Chem. 2005;280:

41 G12/13 mediate Ang II-induced ROS production Fujii, T. et al. J. Biol. Chem. 2005;280:

42 AT1 receptor Oxidative stress Monocytes attraction-mcp-1 Activation CD11b/18 expression Hematopoiesis Endothelial cells Endothelial dysfunction ICAM-1,VCAM-1 Apoptosis Growth factors Cytokines VSMC Contraction Migration Proliferation Apoptosis Cytokines growth factors Matrix metalloproteinase Lipids Oxidation oxldl-uptake Lox-1-expression Coagulation PAI-1 tpa Plaque formation Endothelial dysfunction Plaque rupture-thrombosis

43 Psychological Stress-mediated CV disease RAS, NE, Ach, etc SNS PVN_Hupothalamus CRH HPA Neuropeptides ex. Substance P? Locus Coeruleus NE Ant Pituitary gl POMC: ACTH,GH β-endorphin α-msh Neurogenic Inflammation? Adrenal medulla E & NE RAS ROCK Adrenal cortex corticosteroid Oxidative stress Endoth dysfunction Inflammation Insulin resistance CV remodeling & hypertrophy

Adipose Tissue as an Endocrine Organ. Abdel Moniem Ibrahim, MD Professor of Physiology Cairo University

Adipose Tissue as an Endocrine Organ Abdel Moniem Ibrahim, MD Professor of Physiology Cairo University Functions of Adipose Tissue Adipose tissue expresses and secretes a variety of bioactive peptides,